The Alzheimer's Biomarker Consortium‐Down Syndrome: Rationale and methodology

Abstract

Introduction Adults with Down syndrome (DS) are at exceptionally high risk for Alzheimer's disease (AD), with virtually all individuals developing key neuropathological features by age 40. Identifying biomarkers of AD progression in DS can provide valuable insights into pathogenesis and suggest targets for disease modifying treatments. Methods We describe the development of a multi‐center, longitudinal study of biomarkers of AD in DS. The protocol includes longitudinal examination of clinical, cognitive, blood and cerebrospinal fluid‐based biomarkers, magnetic resonance imaging and positron emission tomography measures (at 16‐month intervals), as well as genetic modifiers of AD risk and progression. Results Approximately 400 individuals will be enrolled in the study (more than 370 to date). The methodological approach from the administrative, clinical, neuroimaging, omics, neuropathology, and statistical cores is provided. Discussion This represents the largest U.S.‐based, multi‐site, biomarker initiative of AD in DS. Findings can inform other multidisciplinary networks studying AD in the general population.

Patterns of glucose hypometabolism in Down syndrome resemble sporadic Alzheimer's disease except for the putamen

“…A total of N = 90 participants with DS (mean age [standard deviation (SD)] = 38.0 [8.30] years) and N = 14 age‐matched siblings without DS (mean age [SD] = 46.6 [13.4] years) were recruited from the University of Wisconsin‐Madison and University of Pittsburgh imaging sites of the ABC‐DS 49 . Age‐matched sibling controls without DS and free of symptoms of dementia were enrolled in the study to act as a biomarker reference group.…”

“…In the current study, 10 participants were classified having MCI‐DS or AD, 77 were cognitively stable (CS‐DS), and the remaining 3 showed cognitive decline but possibly due to non‐AD reasons (eg, life stressors or medical conditions). These diagnostic classifications were performed independent of imaging findings and based on case consensus processing informed by directly administered and caregiver‐reported measures as previously described 49 . The three participants with cognitive decline possibly due to non‐AD reasons evidenced low to moderate Aβ, but no FDG hypometabolism and were included in analyses associating Aβ and FDG with cognition.…”

“…The Alzheimer's Biomarker Consortium–Down Syndrome (ABC‐DS) is an ongoing longitudinal study aimed at characterizing the natural history of AD‐related biomarker change in a large DS cohort 49 . The objective of the current study was to examine the associations among Aβ, glucose metabolism, and early AD‐related cognitive decline and to evaluate the use of FDG for monitoring subtle changes in AD‐related progression.…”

Opportunities, barriers, and recommendations in Down syndrome research

“…In addition, animal and cellular models in development have enabled exploration of therapeutic approaches, with early evidence that immune approaches may be feasible [ 236 ]. Many collaborations and partnerships have been established in recent years to accelerate research on DS-AD, including: Horizon 21, a multisite study in Europe recruiting a trial-ready cohort [ 237 ] The Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) – defining conversion to dementia based on biomarkers [ 238 ] Longitudinal Investigation For the Enhancement of Down Syndrome Research (LIFE-DSR) – an observational cohort study [ 239 ] Alzheimer’s Clinical Trials Consortium - Down Syndrome (ACTC-DS) is preparing to recruit a trial-ready cohort [ 240 ] 3-Star study of the candidate vaccine, ACI-24 sponsored by AC Immune is nearing completion; AC Immune will also soon launch a Phase 2 trial of β-amyloid vaccine in adults with DS [ 241 ] …”

Basal Forebrain Cholinergic Neurons: Linking Down Syndrome and Alzheimer’s Disease

“…Furthermore, no DS studies with PET focus on imaging of BFCNs during preclinical AD. The Alzheimer’s Biomarker Consortium – Down Syndrome (ABC-DS) is an ongoing longitudinal study aimed to better understand AD progression in DS by characterizing AD biomarker change in one of the world’s largest DS research cohorts ( Handen et al, 2020 ). With PET imaging, a pattern of early and prominent amyloid-β retention was identified in the dorsal and ventral striatum ( Handen et al, 2012 ); a pattern which has also been observed in other forms of early-onset AD ( Klunk et al, 2007 ; Remes et al, 2008 ; Villemagne et al, 2009 ; Bateman et al, 2012 ).…”